Outcomes of Daptomycin Plus Ceftaroline Versus Alternative Therapy for Persistent Methicillin-resistant Staphylococcus aureus (MRSA) Bacteremia

Abstract

The purpose of this study was to evaluate both efficacy and safety of combination therapy with daptomycin plus ceftaroline (DAP/CPT) versus alternative therapy in the treatment of persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB). This was a retrospective, single-center study of adult patients who underwent a change in antibiotic therapy for persistent MRSAB. DAP/CPT was compared to alternative therapy after initial treatment with vancomycin or DAP monotherapy was modified. The primary outcome was in-hospital mortality, and several secondary efficacy and safety outcomes were evaluated. A total of 68 patients with persistent MRSAB had initial therapy switched to DAP/CPT (n = 43) or alternative therapy (n = 25). In-hospital mortality was similar with DAP/CPT versus alternative therapy (16.3% vs. 16%; p = 1.0). On average, the total duration of bacteremia was numerically one day less in patients switched to DAP/CPT (11.4 days vs. 12.5 days; p = 0.5). DAP/CPT was de-escalated in 81% of patients after receiving combination therapy for an average of 12.5 days. Secondary outcomes, including rates of adverse events and emergence of antimicrobial resistance, were similar between the two groups. Switching to DAP/CPT after approximately one week of persistent MRSA bacteremia may result in similar clinical outcomes when compared to alternative therapy. Rates of adverse events and emergence of antimicrobial resistance were low without a statistically significant difference observed between DAP/CPT and alternative therapy. These findings, as well as the impact of earlier switch or prolonged treatment with the combination, require further investigation.

1. Introduction

Methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) is a serious illness and associated with complications that result in a high rate of morbidity and mortality [1–3]. Persistent MRSAB has been associated with poor outcomes and serious complications [4,5]. In two large prospective cohort studies, each additional day of MRSAB significantly increased mortality risk compared to that of patients whose MRSAB resolved after a single day [6,7]. The most recent Infectious Diseases Society of America (IDSA) treatment guidelines for MRSAB define treatment failure and persistent bacteremia as lasting >7 days and recommend consideration of high dose daptomycin (DAP) (10 mg/kg/day) in combination with another agent such as linezolid, trimethoprim-sulfamethoxazole, or a β-lactam antibiotic for treatment of persistent MRSAB [8]. However, new data suggests this definition should be reevaluated. In a recent article, Holland et al. state that MRSAB >1 day should be considered a “worry point,” and patients with positive follow-up blood cultures after even 1–2 days of appropriate antibiotic therapy should prompt intensive diagnostic evaluation to identify metastatic foci and be considered for antimicrobial modification such as switching to combination therapy given higher risk of poor outcomes [2]. Currently, there is no recommendation for which specific combination is preferred or the optimal duration of combination therapy. In the last several years, there has been an emergence of new literature supporting combination therapy for persistent MRSAB. Although the in vitro and vivo synergy of several β-lactam antibiotics combined with vancomycin or DAP has been demonstrated for MRSA, many of these agents lack inherent MRSA activity [9–14]. In contrast, ceftaroline (CPT) has activity against MRSA by binding to PBP2a and inhibiting peptidoglycan transpeptidation; it has also been used to successfully treat MRSAB [15–17]. CPT can also enhance DAP cell membrane binding and could be DAP sparing [18–19]. As a result, the combination of DAP/CPT has been investigated and used successfully in cases of persistent or refractory MRSAB [20–22].

There has only been one randomized, open-label pilot study of 40 patients who received DAP/CPT or standard of care (SOC) monotherapy as initial treatment for MRSAB. Treatment with DAP/CPT resulted in a significant reduction of in-hospital mortality (0% vs 26%) resulting in early study termination. The median duration of bacteremia was similar between the two groups. Adverse drug events (ADEs) were also assessed with one patient in the monotherapy group experiencing acute kidney injury (AKI) and another patient experiencing asymptomatic elevated creatinine phosphokinase (CPK). Other ADEs reported include one patient in the combination therapy group experiencing eosinophilic pneumonia [20]. In addition, a large multicenter retrospective matched cohort study compared patients with MRSAB treatment with SOC versus DAP/CPT. The majority of patients in the combination therapy cohort received DAP/CPT as second or third-line therapy. The combination of DAP/CPT resulted in clearance of persistent MRSAB and numerically lower 30-day mortality rate than SOC (8.3% vs 14.2%). In patients with an endovascular source of infection who were switched to combination therapy within 72 hours of index culture, there was a further trend towards decreased mortality (4.3% vs 20.8%) [21]. Overall, assessment of safety outcomes in previous studies is limited. The purpose of this study was to evaluate both efficacy and safety of combination therapy with DAP/CPT versus alternative therapy in the treatment of persistent MRSAB.

2. Materials and methods

2.1. Study Design

This was a retrospective, single-center study of adult patients who underwent a change in antibiotic therapy for persistent MRSAB (defined as blood cultures positive for MRSA despite at least 72 hours of initial anti-MRSA therapy with vancomycin or daptomycin) at a large academic medical center between January 2014 and July 2020. The electronic health record (EHR) was utilized to evaluate for inclusion. At the study institution, MRSAB prompts automatic infectious disease consultation which was consistent throughout the entire study period. Patients discharged on intravenous antimicrobials were followed and monitored by the institution’s outpatient parenteral antimicrobial therapy (OPAT) program.

Individuals lacking repeat blood cultures to document clearance, transferred from an outside hospital, or with polymicrobial bacteremia were excluded. Patient demographic information, microbiological data, diagnostic imaging, antibiotic selection and length of therapy, and length of hospital stay in intensive and general care units were extracted from the EHR. Pitt Bacteremia Score was calculated to quantify the severity of illness. Figure 1 describes the patient screening and inclusion and exclusion criteria.

Figure 1.

Study Population

2.2. Study Outcomes

The primary efficacy outcome was to compare in-hospital mortality of DAP/CPT versus alternative therapy for persistent MRSAB. Secondary efficacy outcomes included total bacteremia duration, time to de-escalation, length of hospital and ICU stay, 90-day all-cause readmission (defined as inpatient admission within 90 days following completion of antimicrobial therapy for MRSA bacteremia), and 90-day MRSA-related readmission (defined as culture proven MRSA-related readmission within 90 days following completion of antimicrobial therapy for MRSA bacteremia). Secondary safety outcomes included incidence of AKI (defined as an increase in serum creatinine (SCr) by greater than or equal to 0.3 mg/dL within 48 hours; or an increase in SCr by greater than or equal to 1.5 times baseline) or renal replacement therapy (RRT) initiation, incidence of Clostridium difficile infection (CDI) (defined as having 3 or more unformed stools over 24 hours or fewer consecutive hours with positive stool test results during or within 90 days after completion of antibiotic therapy), incidence of new extended-spectrum beta-lactamase (ESBL) or vancomycin-resistant enterococci (VRE) infection/colonization (defined as new ESBL/VRE infection/colonization within 90 days of the end of MRSA bacteremia treatment identified via clinical culture data only and not surveillance cultures), and incidence of DAP discontinuation due to elevated CPK (defined as patients whose CPK levels exceed 1000 U/L with symptoms of myopathy and/or 2000 U/L without symptoms).

2.3. Statistical Analysis

Baseline demographics, treatment characteristics, and efficacy and safety outcomes (clinical or microbiological) were compared using the chi-square test (or Fisher’s exact test when the assumptions for the chi-square test were not tenable) for categorical variables, and the two-group t-test (or the Sattherthwaite-corrected t-test when the group variances were unequal) for continuous variables. Distributions of the continuous variables were assessed for normality. Due to skewness in the distributions of a few of these variables, the nonparametric Wilcoxon rank-sum test was also run. In all analyses, this test yielded results that were similar to those obtained from the two-group t-test. Results obtained from the two-group t-test are provided. A P value <0.05 was considered statistically significant in the final analysis. Statistical analysis was conducted using SAS, version 9.4 (SAS Institute, Cary, NC).

3. Results

A total of 68 patients with persistent MRSAB were included in the study and had initial anti-MRSA therapy with vancomycin or daptomycin switched to DAP/CPT (n = 43) or alternative therapy (n = 25). Patient demographics and treatment characteristics for the two groups are outlined in Table 1. There were no statistically significant differences between groups except for higher average baseline creatinine clearance among patients switched to DAP/CPT (42.2 ± 33.7 vs 25.9 ± 21.2; p <0.05). The average DAP dose based on actual body weight was 9.9 mg/kg in patients receiving DAP/CPT and 9.7 mg/kg in the patients who received alternative therapy. The majority (72.0%) of patients in the DAP/CPT group received CPT every 8 hours. The every 12 hour CPT dosing (28.0%) was utilized prior to inclusion of every 8 hour dosing recommendations in institutional guidelines; however, overall study outcomes were not impacted by CPT dosing frequency.

Table 1.

Baseline Demographics and Treatment Characteristics

Characteristic	DAP/CPT (n = 43)	Alternative Therapy (n = 25)	P-value
Age, years,			0.584
mean ± SD	55.0 ± 13.3	57.0 ± 15.5
median ± IQR	55.0 ± 17.0	61.0 ± 29.0
Male gender, n (%)	25 (58.1)	13 (52.0)	0.623
Race, n (%)			0.069
• White	27 (62.3)	10 (40.0)
• Black	16 (37.2)	15 (60.0)
Weight, kg,			0.884
mean ± SD	87.9 ± 28.8	86.6 ± 30.4
median ± IQR	82.5 ± 34.8	75.4 ± 28.4
BMI,			0.843
mean ± SD	31.2 ± 11.7	30.7 ± 10.6
median ± IQR	28.7 ± 12.0	27.2 ± 10.7
CrCl,			0.017
mean ± SD	42.2 ± 33.7	25.9 ± 21.1
median ± IQR	35.0 ± 35.0	19.0 ± 39.0
CrCl, n (%)			0.056
• ≥ 50 mL/min	13 (30.2)	3 (12.0)
• <50 mL/min	24 (55.8)	13 (52.0)
• RRT at baseline	6 (14)	9 (36.0)
Bacteremia source, n (%)			0.209
• Endocarditis	14 (32.6)	5 (20.0)
• Bone/Joint	8 (18.6)	4 (16.0)
• SSTI	6 (14.0)	1 (4.0)
• Catheter-related	6 (14.0)	3 (12.0)
• Other	9 (20.9)	12 (48.0)
Septic emboli, n (%)	16 (37.2)	14 (56.0)	0.132
ICU admission, n (%)	23 (53.5)	13 (52.0)	0.906
Pitt Bacteremia Score,			0.623
mean ± SD	0.9 ± 1.1	1.0 ± 1.2
median ± IQR	1.0 ± 2.0	1.0 ± 2.0
Duration of bacteremia before switching therapy, days,
mean ± SD	6.8 ± 3.9	8.4 ± 5.6	0.228
median ± IQR	6.0 ± 3.0	6.0 ± 7.0
Initial antibiotic therapy, n (%)			1.0
• Vancomycin	42 (97.7)	25 (100.0)
• DAP	1 (2.3)	0 (0.0)
DAP dose (mg/kg),			0.816
mean ± SD	9.9 ± 2.3	9.7 ± 2.2a
median ± IQR	9.6 ± 2.3	10.2 ± 2.7
CPT dosing frequency, n (%)			1.0
• Every 8 hours	31 (72.1)	5 (71.4)b
• Every 12 hours	12 (27.9)	2 (28.6)b
Initial vancomycin trough, mcg/mL,			0.144
mean ± SD	10.9 ± 4.5	13.3 ± 7.1
median ± IQR	11.1 ± 6.0	13.1 ± 8.5
De-escalation of antibiotic, n (%)	35 (81.4)	10 (40.0)	<0.001
Time to de-escalation, days,			0.744
mean ± SD	12.5 ± 7.1	13.9 ± 13.1
median ± IQR	12.0 ± 9.0	8.5 ± 16.0
Total duration of antibiotic therapy, days,			0.696
mean ± SD	40.9 ± 6.2	40.3 ± 6.2
median ± IQR	42.0 ± 0.0	42.0 ± 0.0

Abbreviations: DAP/CPT, daptomycin and ceftaroline; BMI, body mass index; CrCl, creatinine clearance; RRT, renal replacement therapy; SSTI, skin and soft tissue infection; ICU, intensive care unit

^an=14 (number of patients receiving daptomycin as part of alternative therapy)

^bn=7 (number of patients receiving ceftaroline as part of alternative therapy)

All but one patient received vancomycin monotherapy as initial anti-MRSA antibiotic therapy for MRSAB (99.0%). The remaining patient received empiric DAP. The average initial serum vancomycin trough value was 10.9 mcg/mL in the DAP/CPT group and 13.3 mcg/mL in the alternative therapy group. In the alternative therapy group, 12 (48.0%) patients were switched to and completed DAP monotherapy, 5 (20.0%) patients were switched to combination therapy with vancomycin and CPT before de-escalation, and 2 (8.0%) patients were switched to and completed CPT monotherapy. The remaining 6 (24.0%) patients were switched to combination therapy with vancomycin plus gentamicin (3), vancomycin plus DAP (1), DAP plus tigecycline (1), or linezolid monotherapy (1). The average duration of bacteremia before switching therapy was 6.8 ± 3.8 days in the DAP/CPT group and 8.4 ± 5.6 days in the alternative therapy group. The most common sources of bacteremia in the DAP/CPT group were endocarditis (33.0%) followed by bone and joint infection (18.6%). Septic emboli were noted in 16 (37.2%) patients in the DAP/CPT group. Pitt bacteremia score was similar between the two groups.

Table 2 displays the efficacy and safety outcomes from both cohorts. In-hospital mortality was similar with DAP/CPT versus alternative therapy (16.3% vs. 16.0%; p = 1.0). On average, the total duration of bacteremia was approximately one day less in patients switched to DAP/CPT (11.4 days vs. 12.5 days; p = 0.5). Therapy was de-escalated in 81.0% of patients receiving DAP/CPT after receiving combination therapy for an average of 12.5 days. Average total duration of antibiotic therapy was similar in both groups (40.9 vs. 40.3 days; p = 0.7) and consistent with guideline recommended standard of care duration of 4 – 6 weeks for most indications involving persistent MRSAB. Overall, there was no difference in hospital and ICU length of stay, 90-day all-cause readmission, and 90-day MRSA-related readmission between the two cohorts. For our safety outcomes, no statistically significant difference in incidence of AKI or need for RRT initiation, CDI within 90 days, or new ESBL or VRE infection/colonization within 90 days was found. DAP was discontinued for CPK elevation in 2 (5.0%) patients receiving DAP/CPT compared to none in the alternative therapy group.

Table 2.

Efficacy and Safety Outcomes

Outcome	DAP/CPT (n = 43)	Alternative Therapy (n = 25)	P-value
In-hospital mortality, n (%)	7 (16.3)	4 (16.0)	1.0
In-hospital mortality in patients who were de-escalated, n (%)	1 (2.9)a	N/A	N/A
Bacteremia duration, days, mean ± SD
• Total duration of bacteremia			0.507
• mean ± SD	11.4 ± 5.5	12.5 ± 7.2
• median ± IQR	10.0 ± 4.0	10.0 ± 7.0
• Duration of bacteremia after switching therapy			0.511
• mean ± SD	4.6 ± 3.3	4.1 ± 2.8
• median ± IQR	4.0 ± 4.0	4.0 ± 6.0
Duration of therapy after switching to DAP/CPT,		N/A	N/A
mean ± SD	14.3 ± 10.3
median ± IQR	12.0 ± 11.0
Hospital LOS,			0.790
mean ± SD	28.6 ± 15.3	27.5 ± 17.4
median ± IQR	25.0 ± 21.0	22.0 ± 20.0
ICU LOS,			0.801
mean ± SD	8.3 ± 12.7	7.4 ± 17.8
median ± IQR	3.0 ± 12.0	2.0 ± 8.0
90-day all-cause readmission, n (%)	19 (44.2)	9 (36.0)	0.508
90-day MRSA-related readmission, n (%)	4 (9.3)	3 (12.0)	0.702
AKI, n (%)	3 (7.0)	4 (16.0)	0.409
AKI requiring RRT, n (%)	2 (4.7)	0 (0.0)	0.528
C. difficile infection, n (%)	1 (2.3)	1 (4.0)	1.0
New ESBL and/or VRE infection, n (%)	2 (4.7)	1 (4.0)	1.0
DAP discontinued due to CPK elevation/symptoms, n (%)	2 (4.7)	0 (0.0)	0.528

Abbreviations: DAP-CPT, daptomycin and ceftaroline; LOS, length of stay; MRSA, methicillin-resistant Staphylococcus aureus, AKI, acute kidney injury; RRT, renal replacement therapy; ESBL, extended-spectrum beta-lactamase; VRE, vancomycin-resistant enterococci; CPK, creatine phosphokinase

^an=35 (number of patients with de-escalation of antimicrobial therapy in combination group)

4. Discussion

Given the substantial morbidity and mortality associated with persistent MRSAB, it is imperative to explore alternative treatment strategies [1]. In the current treatment paradigm for persistent MRSAB, there are limited clinical data and many unanswered questions. Our data suggests switching to DAP/CPT at approximately one week of persistent MRSAB offers no advantage over common alternative therapies. Three (7.0%) patients were switched to DAP/CPT within 72 hours of index culture and all of these patients survived. Our observation of 0% mortality among three patients switching to DAP/CPT within 72 hours of index culture aligns with other published data suggesting there may be an advantage to initiating this combination therapy earlier in the clinical course in patients with MRSAB [20–21]; however, additional research is needed to corroborate these findings.

The optimal duration of combination therapy for MRSAB is also unclear. A recent retrospective, single center cohort study comparing retained DAP/CPT combination therapy versus de-escalation to vancomycin, DAP or CPT monotherapy within 10 days, found no difference in 60-day bacteremia recurrence, readmission, or inpatient infection-related mortality [23]. In our study, 35 (81.0%) patients receiving DAP/CPT were de-escalated to a single agent after receiving an average of 12.5 days of combination therapy. No differences in efficacy or safety outcomes were noted among patients who underwent de-escalation compared with those who continued DAP/CPT combination therapy. Together, these findings suggest that using an initial period of intensive combination therapy followed by step down to monotherapy according to patient response may be a safe and effective approach for managing cases of persistent or refractory MRSAB [24].

To date, this is the first study specifically evaluating safety outcomes of combination therapy with DAP/CPT. Recent data evaluating combination therapy with vancomycin plus the addition of 7 days of anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin), showed no significant difference in mortality, bacteremia, relapse, or treatment failure. In addition, patients who received the combination of vancomycin plus flucloxacillin experienced a significant increase in incidence of AKI compared to vancomycin monotherapy (35% vs 9.0%) [10]. In the present study, a low rate of AKI and AKI requiring RRT initiation was observed in both groups. Patients in this study received an average of 14.3 days of combination therapy with DAP/CPT. Increased use of broad-spectrum antibiotics, particularly agents with a spectrum of activity comparable to third-generation cephalosporins, raises concern for increased risk of CDI and antimicrobial resistance development [25–27]. We investigated if patients exposed to CPT experienced a higher rate of CDI compared with patients who received alternative agents, but the incidence of CDI in this study was low in both groups. This effect should be studied on a larger scale. Increasing third-generation cephalosporin use has also been associated with an increased incidence of ESBL-producing Enterobacterales [26]. A retrospective analysis from 2012, also demonstrated that ceftriaxone use in the prior month was associated with a higher incidence of VRE bloodstream infection [27]. As a result, we sought to determine if use of DAP/CPT had an impact on antimicrobial resistance development. Only 2 (5.0%) patients developed new ESBL or VRE infection/colonization within 90 days of discontinuing DAP/CPT, indicating no significant risk of antimicrobial resistance development with this combination therapy. Overall, no significant safety signals were noted with the combination of DAP/CPT.

This study adds to the body of literature evaluating treatment and outcomes associated with persistent MRSAB. The combination of DAP/CPT appears to be a relatively safe treatment option; however, the benefit of this combination over alternative therapies remains unclear. Further investigation into the optimal timing of initiation and duration of DAP/CPT may further delineate the role of this combination therapy for persistent MRSAB. Our study has several limitations. These include the retrospective nature of this study that can lead to inherent bias, small sample size limiting the generalizability of our results, and MIC distributions were unknown for different antimicrobials utilized. In addition, we were unable to assess if adequate source control was achieved in all cases. Routine surveillance cultures are not performed at the study institution or in follow up outpatient visits, and as a result, the outcome of incidence of ESBL/VRE colonization/infection is difficult to assess. Side effects associated with extended durations of beta-lactams including neutropenia were not assessed.

5. Conclusion

In this cohort of patients, switching to DAP/CPT after approximately one week of persistent MRSAB resulted in similar efficacy to alternative therapy. Earlier treatment modification may be more beneficial and warrants further investigation. Rates of adverse events and emergence of antimicrobial resistance were low and did not significantly differ between DAP/CPT and alternative therapy. Additional research is needed to adequately assess the implications on the microbiome and hospital ecology with this combination compared with alternative therapies.